title: Enforced expression of MLL-AF4 fusion in cord blood CD34+ cells enhances the hematopoietic repopulating cell function and clonogenic potential but is not sufficient to initiate leukemia.
abstract: Infant acute lymphoblastic leukemia harboring the fusion mixed-lineage leukemia (MLL)-AF4 is associated with a dismal prognosis and very brief latency. Our limited understanding of transformation by MLL-AF4 is reflected in murine models, which do not accurately recapitulate the human disease. Human models for MLL-AF4 disease do not exist. Hematopoietic stem or progenitor cells (HSPCs) represent probable targets for transformation. Here, we explored in vitro and in vivo the impact of the enforced expression of MLL-AF4 in human cord blood-derived CD34(+) HSPCs. Intrabone marrow transplantation into NOD/SCID-IL2Rγ(-/-) mice revealed an enhanced multilineage hematopoietic engraftment, efficiency, and homing to other hematopoietic sites on enforced expression of MLL-AF4. Lentiviral transduction of MLL-AF4 into CD34(+) HSPCs increased the in vitro clonogenic potential of CD34(+) progenitors and promoted their proliferation. Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. However, MLL-AF4 expression was insufficient to initiate leukemogenesis on its own, indicating that either additional hits (or reciprocal AF4-MLL product) may be required to initiate ALL or that cord blood-derived CD34(+) HSPCs are not the appropriate cellular target for MLL-AF4-mediated ALL.
authors.affiliation: Consejería de Salud-Universidad de Granada, Granada, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Montes
authors.forename: Verónica
authors.initials: V
authors.lastname: Ayllón
authors.forename: Ivan
authors.initials: I
authors.lastname: Gutierrez-Aranda
authors.forename: Isidro
authors.initials: I
authors.lastname: Prat
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Hernández-Lamas
authors.forename: Laura
authors.initials: L
authors.lastname: Ponce
authors.forename: Silvia
authors.initials: S
authors.lastname: Bresolin
authors.forename: Geertruy
authors.initials: G
authors.lastname: Te Kronnie
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
authors.forename: Clara
authors.initials: C
authors.lastname: Bueno
authors.forename: Pablo
authors.initials: P
authors.lastname: Menendez
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology
chemical_list: D017931:DNA Primers; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein